ABSTRACT
OBJECTIVE: Central feeding regulation involves both anorectic and orexigenic pathways. This study examined whether targeting both systems could enhance feeding inhibition induced by anorectic neuropeptides. RESEARCH METHODS AND PROCEDURES: Experiments were carried out in 24-hour fasted rats. Intracerebroventricular (ICV) injections were accomplished through stereotaxically implanted cannulae aimed at the lateral cerebral ventricle. Food intake of standard rat chow pellets was subsequently recorded for 2 hours. RESULTS: Blockade of orexigenic central opioids and neuropeptide Y (NPY) by ICV naloxone (25 microg) or the NPY receptor antagonist [D-Trp32]NPY (NPY-Ant; 10 micro g) powerfully augmented the feeding suppression induced by ICV glucagon-like peptide 1 (7-36)-amide (GLP-1; 10 microg) or xenin-25 (xenin; 15 microg) in 24-hour fasted rats. Most importantly, in combination with naloxone or NPY-Ant, even a low and ineffective dose of GLP-1 (5 microg) caused a 40% reduction of food intake, which was augmented further when both antagonists were given in combination with GLP-1. The combination of GLP-1 (5 microg) and xenin (10 microg) at individually ineffective doses caused a 46% reduction of food intake, which was abolished at a 10-fold lower dose. This ineffective dose, however, reduced food intake by 72% when administered in combination with naloxone and NPY-Ant. DISCUSSION: Targeting up to four pathways of feeding regulation in the central nervous system by blockade of endogenous feeding stimuli and simultaneous administration of anorectic neuropeptides potentiated reduction of food intake. This raises a promising perspective for treatment of obesity.
Subject(s)
Appetite Depressants/administration & dosage , Eating/drug effects , Eating/physiology , Neuropeptides/administration & dosage , Animals , Glucagon/administration & dosage , Glucagon-Like Peptide 1 , Homeostasis/drug effects , Male , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Neuropeptide Y/antagonists & inhibitors , Neurotensin , Peptide Fragments/administration & dosage , Peptides/administration & dosage , Protein Precursors/administration & dosage , Rats , Rats, Wistar , Receptors, Neuropeptide Y/antagonists & inhibitorsABSTRACT
Glucagon-like peptide 1-(7-36) amide (GLP-1) potently inhibits rat feeding behavior after central administration. Because third ventricular injection of GLP-1 appeared to be less effective than lateral ventricular injection, we have reexamined this issue. In addition, we attempted to identify brain regions other than the paraventricular nucleus of the hypothalamus that are sensitive toward GLP-1-induced feeding suppression. Finally, we examined the local role of endogenous GLP-1 by specific GLP-1 receptor blockade. After lateral ventricular injection, GLP-1 significantly inhibited food intake of 24-h-fasted rats in a dose-dependent fashion with a minimal effective dose of 1 microg. After third ventricular injection, GLP-1 (1 microg) was similarly effective in suppressing food intake, which extends previous findings. Intracerebral microinjections of GLP-1 significantly suppressed food intake in the lateral (LH), dorsomedial (DMH), and ventromedial hypothalamus (VMH), but not in the medial nucleus of the amygdala. The minimal effective dose of GLP-1 was 0.3 microg at LH sites and 1 microg at DMH or VMH sites. LH microinjections of exendin-(9-39) amide, a GLP-1 receptor antagonist, at 1 or 2.5 microg did not alter feeding behavior in 24-h-fasted rats. In satiated animals, however, a single LH injection of 1 microg exendin-(9-39) amide significantly augmented food intake, but only during the first 20 min (0.6 vs. 0.1 g). With three repeated injections of 2.5 microg exendin-(9-39) amide every 20 min, 1-h food intake was significantly increased by 300%. These data strongly support and extend the concept of GLP-1 as a physiological regulator of food intake in the hypothalamus.